Abstract ? Project 1: Immune correlates of protection against congenital CMV Cytomegalovirus is the most common congenital infection, complicating 40,000 births in the U.S. annually. Up to 25% of infants born with CMV will have permanent neurologic disabilities, including hearing loss. Development of a maternal vaccine that induces effective preconception immunity offers the best hope of eliminating congenital CMV (cCMV), yet this strategy faces significant hurdles. Among these are the incomplete protection conferred by natural immunity and an incomplete understanding of what constitutes protective CMV immunity. While CMV-seropositive mothers have a reduced risk of vertical CMV transmission upon reinfection compared to CMV-nave mothers with primary infection during pregnancy, they can still transmit virus. Because natural immunity is only partially protective, an effective vaccine will need to induce a more robust or modified preconception immune response. To investigate immune protection against cCMV, we established a novel nonhuman primate (NHP) model of placental cCMV transmission in rhesus monkeys, and showed that maternal CD4+ T cell responses are critical in protection. A lag in the development of CMV-neutralizing antibodies and cytotoxic T lymphocytes was associated with a more severe outcome; and passive infusion of CMV seronegative dams with hyperimmune globulin prior to rhesus CMV inoculation protected against fetal loss. Although these studies highlight the importance of maternal immunity, the contribution of individual arms of the immune system in preventing cCMV remains unclear. Project 1 will therefore test the hypothesis that both humoral and cellular maternal CMV-specific immune responses are required to prevent cCMV infection. Defining the precise contribution of individual components of anti-CMV immunity to (i) inhibition of placental transmission and (ii) modulation of fetal disease is necessary to determine whether CMV vaccines should target one or both arms of the adaptive immune system. In concert with Cores 1-4, Project 1 will use a combination of genetic analysis, in vivo depletion experiments, and exhaustive immune and virologic evaluation to characterize transmitted virus variants and determine the contribution of CMV-specific humoral and cellular immune responses in protecting against cCMV in the NHP model. Our specific aims are as follows: Aim 1: Characterize placental CMV transmission during primary infection in immunocompetent dams and define maternal and fetal immune correlates of protection against transmission; Aim 2: Determine the contribution of B and CD8+ T cell immunity to protection against placental CMV transmission; Aim 3: Determine whether vaccine-induced pre-conception T cell immunity is sufficient to lower plasma viremia and protect against placental CMV transmission or fetal loss in primary infection. These studies will provide insight in to the correlates of immune protection against placental CMV transmission in a highly relevant model of cCMV infection and inform the immunologic targets of an effective CMV vaccine.